US2022227700A1PendingUtilityA1
Hdac3 catalytic inhibitor development and uses thereof
Assignee: DANA FARBER CANCER INST INCPriority: Jun 13, 2019Filed: Jun 12, 2020Published: Jul 21, 2022
Est. expiryJun 13, 2039(~12.9 yrs left)· nominal 20-yr term from priority
C07D 215/38A61P 35/00C07D 209/40C07D 333/66C07C 317/32C07D 213/40C07D 295/135C07D 277/82C07D 233/61C07C 233/81C07D 211/58C07D 231/40C07D 209/86C07D 217/02C07D 495/04
49
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Provided herein are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat diseases or disorders associated with HDAC3 activity.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
R is selected from the group consisting of fluoro, bromo, chloro, —NH 2 , —OH, —SH, —NHR 3 , —N(R 3 ) 2 , OR 3 , SR 3 , NO 2 , thienyl, and CN;
R 1 is selected from the group consisting of fluoro, bromo, chloro, —NH 2 , —OH, —SH, —NHR 3 , —N(R 3 ) 2 , OR 3 , SR 3 , NO 2 , thienyl, and CN;
R 2 is selected from the group consisting of C 6 -C 10 aryl, C 5 -C 13 heteroaryl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 1 -C 6 alkyl-C 6 -C 10 aryl, C 1 -C 6 alkyl-C 5 -C 13 heteroaryl, C 1 -C 6 alkyl-C 3 -C 10 cycloalkyl, C 1 -C 6 alkyl-C 3 -C 10 heterocycloalkyl, and -linker-biotin;
wherein C 5 -C 10 heteroaryl, C 6 -C 10 aryl, and C 1 -C 6 alkyl are optionally substituted with one to three halo, phenyl, —C(O)Me, —OMe, methyl, NO 2 , —SO 2 Me, Ce heterocycloalkyl, C 5 -C 6 heteroaryl, and CF 3 ; and
R 3 is independently, at each occurrence, selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
2 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R is selected from the group consisting of fluoro, bromo, chloro, —NH 2 , —OH, and —SH;
R 1 is selected from the group consisting of fluoro, bromo, chloro, —NH 2 , —OH, and —SH;
R 2 is C 6 -C 10 aryl or C 5 -C 13 heteroaryl; and
R 3 is H or C 1 -C 6 alkyl.
3 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R is fluoro and R 1 is —NH 2 .
4 . The compound of any of claims 1 - 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —CH 2 C 5 -C 13 heteroaryl.
5 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula II:
or a pharmaceutically acceptable salt thereof;
wherein:
R 2 is selected from the group consisting of C 6 -C 10 aryl, C 5 -C 10 heteroaryl, or linker-biotin, wherein C 6 -C 10 aryl is optionally substituted with halo or SO 2 Me;
R 4 is selected from the group consisting of fluoro, bromo, chloro, —NH 2 , —OH, and —SH; and
R 5 is selected from the group consisting of fluoro, bromo, chloro, —NH 2 , —OH, and —SH.
6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 5 -C 10 heteroaryl, R 4 is fluoro, and R 5 is —NH 2 .
7 . The compound of claim 5 , wherein R 2 is
8 . The compound of any of claims 1 - 6 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Formula II is a compound of Formula III:
9 . The compound of claim 6 , wherein the compound of Formula II is a compound of Formula IV:
or a pharmaceutically acceptable salt thereof.
10 . A pharmaceutical composition comprising a compound according to any one of claims 1 - 9 , or a salt thereof, and at least one pharmaceutically acceptable carrier.
11 . A method of selectively inhibiting the activity of histone deacetylase 3 (HDAC3) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to any one of claims 1 - 9 or a composition according to claim 10 .
12 . A method of treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to any one of claims 1 - 9 or a composition according to claim 10 .
13 . The method of claim 12 , wherein the cancer is Medulloblastoma, rhabdomyosarcoma, Hodgkin lymphoma, acute myeloid leukemia, myelodysplastic syndrome, pancreatic cancer, colon cancer, ovarian cancer, lung cancer, stomach cancer, a muscle cancer, a bone cancer, or a skin cancer.
14 . The method of claim 13 , wherein the cancer is rhabdomyosarcoma.
15 . The method of claim 13 , wherein the cancer is alveloar rhabdomyosarcoma
16 . The method of claim 13 , wherein the cancer is pediatric rhabdomyosarcoma.
17 . A method of treating a neurodegenerative disease in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to any one of claims 1 - 9 or a composition according to claim 10 .
18 . The method of claim 17 , wherein the neurodegenerative disease is Spinal Muscular Atrophy, polyglutamine-related diseases, or amyotrophic lateral sclerosis.
19 . The method of claim 18 , wherein the polyglutamine-related disease is Huntington disease, dentatorubral-pallidoluysian atrophy, or spinocerebellar ataxia type 6 (SCA6).
20 . A process for preparing a compound of Formula V:
comprising reacting a corn und of Formula VI:
with an acid in a solvent;
wherein
R 4 is selected from the group consisting of fluoro, bromo, and chloro; and
R 6 is a protecting group selected from the group consisting of acetyl (Ac), benzyl (Bn), tert-butyloxycarbonyl (Boc), benzoyl (Bz), carboxybenzyl (Cbz), carbamate, 3,4-dimethoxy-benzyl (DMPM), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz), 4-nitrobenzylsulfonyl (Nos), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), 4-toluenesulfonyl (Tos), and trichloroethyl chloroformate (Troc).
21 . The process of claim 20 , wherein the acid is hydrochloric acid.
22 . The process of claim 20 or 21 , wherein the solvent is dioxane.
23 . The process of any one of claims 20 - 22 , wherein R 6 is tert-butyloxycarbonyl (Boc).
24 . The process of any one of claims 20 - 23 , wherein R 4 is fluoro.
25 . A process for preparing a compound of Formula VI:
comprising reacting a compound of Formula VII:
with a compound of Formula VIII:
in the presence of a peptide coupling reagent, a base, and a solvent;
wherein
R 4 is selected from the group consisting of fluoro, bromo, and chloro; and
R 6 is a protecting group selected from the group consisting of acetyl (Ac), benzyl (Bn), tert-butyloxycarbonyl (Boc), benzoyl (Bz), carboxybenzyl (Cbz), carbamate, 3,4-dimethoxy-benzyl (DMPM), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz), 4-nitrobenzylsulfonyl (Nos), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), 4-toluenesulfonyl (Tos), and trichloroethyl chloroformate (Troc).
26 . The process of claim 25 , wherein the peptide coupling reagent is 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU).
27 . The process of claim 25 or 26 , wherein the base is N,N-diisopropylethyl amine (DIPEA or Hunig's base).
28 . The process of any one of claims 25 - 27 , wherein the solvent is dimethylformamide.
29 . The process of any one of claims 25 - 28 , wherein R 6 is tert-butyloxycarbonyl (Boc).
30 . The process of any one of claims 25 - 29 , wherein R 4 is fluoro.
31 . A process for preparing a compound of Formula VII:
comprising treating a compound of Formula IX:
with hydrogen gas in the presence of a palladium catalyst and a solvent or mixture of solvents;
wherein
R 4 is selected from the group consisting of fluoro, bromo, and chloro; and
R 6 is a protecting group selected from the group consisting of acetyl (Ac), benzyl (Bn), tert-butyloxycarbonyl (Boc), benzoyl (Bz), carboxybenzyl (Cbz), carbamate, 3,4-dimethoxy-benzyl (DMPM), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz), 4-nitrobenzylsulfonyl (Nos), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), 4-toluenesulfonyl (Tos), and trichloroethyl chloroformate (Troc).
32 . The process of claim 31 , wherein the palladium catalyst in 10% palladium on carbon.
33 . The process of claim 31 or 32 , wherein the solvent is a mixture of ethanol and ethyl acetate.
34 . The process of any one of claims 31 - 33 , wherein R 4 is fluoro.
35 . The process of any one of claims 31 - 34 , wherein R 6 is tert-butyloxycarbonyl (Boc).
36 . A process for preparing a compound of Formula IX:
comprising reacting a compound of Formula X:
with a protecting group reagent and a base, or combination of bases, in a solvent:
wherein
R 4 is selected from the group consisting of fluoro, bromo, and chloro; and
R 6 is a protecting group selected from the group consisting of acetyl (Ac), benzyl (Bn), tert-butyloxycarbonyl (Boc), benzoyl (Bz), carboxybenzyl (Cbz), carbamate, 3,4-dimethoxy-benzyl (DMPM), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz), 4-nitrobenzylsulfonyl (Nos), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), 4-toluenesulfonyl (Tos), and trichloroethyl chloroformate (Troc).
37 . The process of claim 36 , wherein the protecting group reagent is di-tert-butyl dicarbonate (Boc 2 O) and R 6 is tert-butyloxycarbonyl (Boc).
38 . The process of claim 36 or 37 , wherein the base is a combination of 4-dimethylaminopyridine (DMAP) and is N,N-diisopropylethyl amine (DIPEA or Hünig's base).
39 . The process of any one of claims 36 - 38 , wherein the solvent is dichloromethane (DCM).
40 . The process of any one of claims 36 - 39 , wherein R 4 is fluoro.
41 . A process for preparing a compound of Formula VIII:
comprising reacting a compound of Formula XI:
with a base in a solvent;
wherein R 7 is C 1 -C 6 alkyl.
42 . The process of claim 41 , wherein the base in sodium hydroxide (NaOH).
43 . The process of claim 41 or 42 , wherein the solvent is methanol.
44 . The process of any one of claims 41 - 43 , wherein R 7 is —CH 3 .
45 . A process for preparing a compound of Formula XI:
comprising reacting a compound of Formula XII:
with a compound of Formula XIII:
in the presence of a peptide coupling reagent, a base, and a solvent; wherein R 7 is C 1 -C 6 alkyl.
46 . The process of claim 45 , wherein the peptide coupling reagent is 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU).
47 . The process of claim 45 or 46 , wherein the base is N,N-diisopropylethylamine (DIPEA or Hünig's base).
48 . The process of any one of claims 45 - 47 , wherein the solvent is dimethylformamide (DMF).
49 . The process of any one of claims 45 - 48 , wherein R 7 is —CH 3 .
50 . A process for preparing a compound of Formula IV:
comprising reacting a compound of Formula XIV:
with a compound of Formula XV:
in the presence of a peptide coupling reagent and a base in a solvent, then further reacting the product of the above reaction with an acid;
wherein
R 4 is selected from the group consisting of fluoro, bromo, and chloro; and
R 6 is a protecting group selected from the group consisting of acetyl (Ac), benzyl (Bn), tert-butyloxycarbonyl (Boc), benzoyl (Bz), carboxybenzyl (Cbz), carbamate, 3,4-dimethoxy-benzyl (DMPM), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz), 4-nitrobenzylsulfonyl (Nos), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), 4-toluenesulfonyl (Tos), and trichloroethyl chloroformate (Troc).
51 . The process of claim 50 , wherein the peptide coupling reagent is 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).
52 . The process of claim 50 or 51 , wherein the base is N,N-diisopropylethylamine (DIPEA or Hünig's base).
53 . The process of any one of claims 50 - 52 , wherein the solvent is dimethylformamide (DMF).
54 . The process of any one of claims 50 - 53 , wherein the acid is hydrochloric acid (HC).
55 . The process of any one of claims 50 - 54 , wherein R 4 is fluoro and R 6 is tert-butyloxycarbonyl (Boc).
56 . A process for preparing a compound of Formula XIV:
comprising reacting a compound of Formula XVI:
with a base in a solvent;
wherein
R 4 is selected from the group consisting of fluoro, bromo, and chloro; and
R 6 is a protecting group selected from the group consisting of acetyl (Ac), benzyl (Bn), tert-butyloxycarbonyl (Boc), benzoyl (Bz), carboxybenzyl (Cbz), carbamate, 3,4-dimethoxy-benzyl (DMPM), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz), 4-nitrobenzylsulfonyl (Nos), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), 4-toluenesulfonyl (Tos), and trichloroethyl chloroformate (Troc).
57 . The process of claim 56 , wherein the base in sodium hydroxide (NaOH).
58 . The process of claim 56 or 57 , wherein the solvent is methanol (MeOH).
59 . The process of any one of claims 56 - 58 , wherein R 4 is fluoro and R 6 is tert-butyloxycarbonyl (Boc).
60 . A process for preparing a compound of Formula XVI:
comprising reacting a compound of Formula XVII:
with a compound of Formula VII:
in the presence of a peptide coupling reagent and a base in a solvent;
wherein
R 4 is selected from the group consisting of fluoro, bromo, and chloro; and
R 6 is a protecting group selected from the group consisting of acetyl (Ac), benzyl (Bn), tert-butyloxycarbonyl (Boc), benzoyl (Bz), carboxybenzyl (Cbz), carbamate, 3,4-dimethoxy-benzyl (DMPM), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz), 4-nitrobenzylsulfonyl (Nos), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), 4-toluenesulfonyl (Tos), and trichloroethyl chloroformate (Troc).
61 . The process of claim 60 , wherein the peptide coupling reagent is 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).
62 . The process of claim 60 or 61 , wherein the base is N,N-diisopropylethylamine (DIPEA or Hünig's base).
63 . The process of any one of claims 60 - 62 , wherein the solvent is dimethylformamide (DMF).
64 . The process of any one of claims 60 - 63 , wherein R 4 is fluoro and R 6 is tert-butyloxycarbonyl (Boc).
65 . The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of
or a pharmaceutically acceptable sa thereof.Join the waitlist — get patent alerts
Track US2022227700A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.